Tetrahydrofurfuryl aminoesters

ABSTRACT

The present invention relates to substituted tetrahydrofurfuryl aminoesters. The novel tetrahydrofurfuryl dialkyl aminoesters are represented by the formula   IN WHICH R is a member of the group formed by the 2-naphthyl, 2naphthyl substituted with methoxy in the 6-position and 5,6,7,8tetrahydro-1-naphthyl radicals. The addition salts with the terapeutically acceptable acids, the starting and intermediate products of these aminoesters, also form the subject of the invention. The novel aminoesters and their salts, endowed with peripheral and cerebral vasodilatory properties, are of particular interest in human therapeutics.

gliliifi Szarvasi tes atem 1 [451 Mar. 18, 1975 TETRAHYDROFURFURYLAMINOESTERS [75] Inventor: Etienne Szarvasi,

Charbonnieres-les-Bains, France [73] Assignee: Lipha, Lyonnaiselndustrielle Pharmaceutique, Lyon, France [22] Filed: July 2.7, 1972[21] Appl. No: 275,638

[30] Foreign Application Priority Data July 29, 1971 France 71.27823[52] 11.8. (.I 260/3475, 260/347.3, 260/651, 424/285 [51] int. Cl C07d5/04 58 Field of Search 1. 260/3475, 347.4

[56] References Cited UNITED STATES PATENTS 3,282,965 11/1966 Szarvasiet al7 260/3474 3,334,096 8/1967 Szarvasi et a] 260/3474 PrimaryE.\amt'nerHenry R. Jiles Assistant Examiner-Bernard Dentz Attorney,Agent, or Firm-Browdy and Neimark [57] ABSTRACT The present inventionrelates to substituted tetrahydrofurfuryl aminoesters. The noveltetrahydrofurfuryl dialkyl aminoesters are represented by the formulacut,

n on CH 002C112 CHEN in which R is a member 01 the group formed by theZ-naphthyl, Z-naphthyl substituted with methoxy in the 6-position and5,6,7,8-tetrahydro-l-naphthyl radicals. The addition salts with theterapeutically acceptable acids, the starting and intermediate productsof these aminoesters, also form the subject of the invention.

The novel aminoesters and their salts, endowed with peripheral andcerebral vasodilatory properties, are of particular interest in humantherapeutics 6 Claims, N0 Drawings TETRAHYDROFURFURYL AMINOESTERS Thepresent invention relates to substituted tetrahydrofurfuryl aminoesters,the processes for the preparation thereof and their applications. It isalso concerned with obtaining initial products and intermediate productsin the synthesis of these novel aminoesters.

A certain number of aminoesters derived from 3-(1- naphthyl)2-(Z-tetrahydrofurfuryl)-propionic acid are known which are endowed withvasodila tory and antispasmodic properties, particularly in the US. Pat.No.

vention that the substitution in the l-position by the naphthalenicnucleus is not essential and that the saturation of one of the nuclei ofthe naphthyl radical permits the biological activity to be preserved.

The novel tetrahydrofurfuryl dialkylaminoesters according to theinvention have a double activity as peripheral vasodilators and cerebralvasodilators without a hypotcnsive effect and they are represented bythe formula:

/C l-l R-CH-CH-COCH-CH -N in which R is a member of the group formed bythe 2- naphthyl radical, the 2-naphthyl radical substituted with alkoxysuch as methoxy in the 6-position and 5,6,7,8-tetrahydro-l-naphthylradical.

It has been discovered that the substitution in the 6- position of thenaphthalene nucleus by an alkoxy radical, particularly a methoxyradical, has a favorable influence on the therapeutic activity, while asubstitution in the 4-position can correspond to compounds which can beconsidered as practically inactive, such as the case of2-N-diethylaminoethyl-3-(4-chloro-lnaphthyl)2-(2-tetrahydrofurfuryl)-propionate.

The derivatives of these compounds, which also form the subject of theinvention, are their addition salts with the acids acceptable fortherapeutic uses.

The novel compounds can be obtained according to the invention bycondensation of a carboxylic acid of formula R CH CH COOH c a 2 5 Y 4onN in which Y is a halogen, in the presence of an alkali agent. Accordingto one method of procedure, the condensation is carried out under heatin the presence of an alkaline mineral agent, such as potassiumcarbonate, in an alcoholic solvent medium, such as isopropanol.

For preparing the acid oxalates of the compounds of formula I, theaminoesters as previously obtained are salified with oxalic acid inacetone medium.

The disubstituted carboxylic represented by the formula ll, in which Ris the possibly methoxy substituted Z-naphthyl radical, are obtained bysaponification and decarboxylation by an alkali in the presence of analcohol, preferably benzyl alcohol, alkyl malonates of formula:

R-cii cooa COOR - R-CH2 OOC H COOC2H5 in which R has the same meaning aspreviously, which are capable of being used particularly as intermediateproducts in the preparation of the aminoesters of formula l, are noveland for this reason form part of the invention.

A process of preparation has also been found, with which it is possibleto obtain l-chloromethyl-5,6,7,8- tetrahydronaphthalene in a pure state,free from its isomer, which is a starting product in the preparation of:ethyl-a-IS,6,7,8-tetrahydro-l-naphthylmethyl/a-(2-tetrahydrofurfuryl)-malonate.

The l-chloromethyl-5,6,7,8-tetrahydronaphthalene in pure form and assuch a new industrial product is obtained by reacting(5,6,7,8-tetrahydro-lnaphthyl)methanol with thionyl chloride in thepresence of pyridine and in a chlorinated organic solvent 3 4 medium.The product, obtained by distillation with a boiling mixture of 100 mlof hexane 30 ml of ethyl purity of 86 is recrystallized in hexane,yielding the acetate. After cooling, there are obtained in two lots:chlorinated derivative with a purity of 100 by va- 256 g of whitecrystals, of melting point F 8590C p ur phas chroma ographywith a yieldof 61 (theoretical yield: 42 g).

Examples illustrating the invention in non-limiting 5 Acidity IndCalculated: 197. Found: 193. m nner re gi en el The product is used assuch in the sequence of operations, but for the analytical specimen, itis purified by EXAMPLE 1 changing to its methyl ester c,,n,,o,, M.w.298.37, Ethyl-a-(2-naphthylmethyl)-(2-tetrahydrofurfuryl)- prepared asfollows: the following are heated under remalonate l flux for 6 hours:31 g (mol/9.l) of the above acid in i ii coeti CH0 H co C ll

a 2 5 New. 384.45

4.5 g (mol/l2) of sodium mcthylate and 50 ml of 140 ml of methanol and 7ml of concentrated H 80 ethyl carbonate are placed in a reactor. 19.5 gThe usual treatment yields g of YCHOW liquid of (mOl/l2.5) ofethyl-(2-tetrahydrofurfuryl)-malonate boiling p n -P -n.5 with a yieldof are added thereto. A gentle exothermal reaction is pro- (73(theorellcal yleldi g)- VPC XE 0 (T 260):

duced, with development of a yellow colouring. Heat- Single P infraredSpectrum conforms- The above ing under reflux takes place for minutesand the soester, when SEIPOHifiCd. yi s th C rresponding acid. lutionbecomes brown. After cooling, 15 g (mol/l 1.7) For this P p there areheated Undcr fcflUX for 5 of 2-ehloromethyl naphthalene are introduceddrophoursi g ("ml/139) of thc abovc ester, 50 mIOF wise. Heating underreflux takes place for 8 hours; with 30 ethyl alcohol and 5 (426 g "101/2- of 85 the commencement of the heating, the formation of so- Afterevaporanng the alcoholi the Crude P di hl id i confi ed Aft li water itassium salt is dissolved in water. The aqueous solution added, theOrganic layer is poured off and d i d Over is washed with ether.Acidification is carried out with anhydrous di Sulphate, hydrochloricacid. An oily precipitate is obtained,

Distillation of the organic layer permits 18.2 g of a becomes Solid f yi whcn it is talfcn viscous yellow liquid to be isolated, the saidliquid hav- P ether- After filtermg 11th SUCUO" and Washmg i a b ilipoint 1 200C i h a i l f 555 with diisopropyl ether, there is obtained afirst lot of 5.9 (th reti l i ld 323 g of white product with a meltingpoint of 9799C and Vapour phase chromatography (XE 6O T 265), a secondlot of 7.3 g of white product, m.p. =60-65C. single peak. T)he yield is13.2 g, i.e. 64.5 (theoretical yield: 20.5

The first lot, after recrystallization from hexane and diisopropyl ether(1:1) melts at lO4l05C. White Gravimetric analysis Crystals- C '7: HCalculmed 7'33 733 A.I.: Calculated: 197. Found: 196. Found 71.81 7.35[.R. CO at 1740 cm 1 The infrared spectrum obtained can be superimposedGravimetric a sis on the spectrum of its l-naphthyl isomer. C 72 H 5OCalculated 76.04 7.09 EXAMPLE 2 Found 76.00 7.073-(2-Naphthyl)-2-(2-tetrahydrofurfuryl)-propionie acid The acid seems toexist in two forms: threo and cryll Cll CC H c ii e- HZJ l M.w 26 .)5

57 g l/575) f th -(2- h h l h -(2 thro. The second lot probablyrepresents a mixture. tetrahydrofurfuryl)-malonate 20 g f 85 KOH (17 Thefirst lot alone was prepared for the analysis. g= mol/3.3) are heatedunder reflux for 8 hours in 300 Potassium lli -p. 238240C. ml of benzylalcohol. The benzyl alcohol lStlllVGll off EXAMPLE 3 under vacuum. Thecrude potassium salt is dissolved in water. The aqueous solution iswashed with benzene p y and acidified. An Oll precipatates. It isdissolved in the tetrahydrofurfuryl -Pr0piOnme 2 CH C11 14.6 g(mol/9.45) of potassium carbonate are placed in 130 ml of isopropanoland there are added there to g (mol/l 1.45) of 2-chlorethyl diethylaminchydro chloride, followed by the solution of g (mol/l1.38) of 3-(2-naphthyl 2-tetrahydrofurfuryl )propionic acid in 40 ml of tepidisopropanol. Heating under reflux takes place for 8 hours. Afterevaporation to dryness, the residue is taken up in water made acid withhydrochloric acid, washed with ether and the aqueous layer is madealkaline with sodium hydroxide and then extracted with ether. Bydistillation, there are obtained 14 g of a light yellow liquid ofboiling point b.p. 195200C, with a yield of 41.6 (theoretical yield:33.6 g).

With the second distillation, the boiling point is bp 204-206C.

Gravimetric Analysis Calculated Found 1740 cm: CO ester 1500 cm: 1600cm: aromatic vibration 3050 cm: benzenic CH Acid oxalate: C H NO M.w.473.55.

11.3 g (mol/34) of the above base are dissolved in 15 ml of acetone.This solution is introduced dropwise into a solution of 3.7 g (mol/34)of twice-hydrated oxalic acid in 22 ml of acetone. 10 g of whitecrystals are ob- Gravimetric analysis C /0 H Z N 72 Calculated 65.957.45 2.95 Found 65.91 7.47 3.00

The infrared spectrum of the first lot can be practically superimposedon its isomer, l-naphthyl, known under the commercial mark of Praxilene.

Gravimetric analysis (first lot) C 7r H 72 N Calculated 65.95 7.45 2.95Found 65.95 7.48 2.94

EXAMPLE 4 l-Chloromethyl-5 ,6,7,8-tetrahydronaphthalene 61 g (0.376 mol)of (5,6,7,8-tetrahydro-1- naphthyl)methanol with a purity of 78 7c aredissolved in 450 ml of chloroform, in the presence of 35 g (0.38 mol) ofpyridine. ml of thionyl chloride in solution in 30 ml of chloroform areintroduced dropwise at between 30 and 40C into the solution which isobtained and this is heated under reflux for 6 hours. After partialevaporation of the chloroform and the thionyl chloride excess, washingis carried out with water and with a sodium bicarbonate solution,followed by drying over anhydrous sodium sulphate. Distillation of theoily residue permits the isolation of a liquid of boiling point b.p. 8l83C, with a purity of 86 (vapour phase chromatography), and this istaken up in 150 ml of hot hexane. The crystallisation is seeded byscratching with a glass rod. There are isolated 29.5 g of a productmelting at 5152C, with a yield of 56 (theoretical yield 53 g, dependingon the degree of purity of the starting product). Vapour phasechromatography confirms a purity of Gravimetric analysis C% 11% Cl%Calculated 73.12 7.25 19.62 Found 73.10 7.25 19.65

EXAMPLE 5 Ethyl-a-( 5 ,6,7 ,S-tetrahydro-1-naphthylmethyl)-a-(2-tetrahydrofurfuryl)-malonate CH CO C H 12.5 g (0.232 mol) of sodiummethylate are The distillate, left for a few days at ambienttemperapended in 150 ml of distilled ethyl arbon 55 g ture, starts tocrystallise. 50 ml of hexane and 10 ml of (0.226 mol) ofethyl-(2-tetrahydr0furfur l)- l ethyl acetate are added thereto. Whitecrystals are separe introduced. Heating under reflux takes place forflfated out, -P- 88049000 one hour. At the temperature of 70C, there areadded 5 After recrystallisation y acetate-hexanfilY the 41 g (0.228 mol)of 1-chloromethyl-5,6,7,8-tetrahyconstants are as follows:dronaphthalene in 120 ml of ethyl carbonate, followed M.p. 9093C byheating under reflux for 8 hours. Water is added in Acidity iflCalculatedl FOurldI the cold, followed by dilute hydrochloric acid (pHInfrared CO at 1700 cm" 7). The organic layer is dried and distilled. 10

ll: 3 g b.p. l8ll85C I Vapour phase chromatography fractions l and II MH 7 identical and pure at 100 The analytical sample, C l l t d 73,3 68.38 twice distilled, has a boiling point hp. l83l 84C. Found 7498 8.35

Yield 62 g= 70 (theoretical yield 88.5 g).

- Subsequently, the crude acid, not crystallised, is used as such. It isalso possible to obtain the crystalline form Gra t analy of the acidfrom the crude, undistilled oil, by adding a C 0/1 H mixture of hexaneand ethyl acetate. Calculated 71.1 i 8.30

N-2-diethylaminoethyl-3( 5 ,6,7,8-tetrahydrol Infrared CO at (m-1naphthyl)-2-(Z-tetrahydrofurfuryl)-propionate O H C ll NO I H 5 a? 3-Gl-l'-CH-C-O-CH -C -N 2 a 2 C l-l M-w. 87.54

EXAMPLE 6 8.1 g (0.058 mol) of potassium carbonate are sus- 3 (5,67,8tetrahydro 1 naphthy1) 2 (2 tetrahydmfur 4O pended in 135 ml ofisopropanol and there are added furyl) propionic acid thereto 13 g(0.096 mol) of N-diethylammo2- chlorethane and a solution of 27 g (0.094mol) of crude acid from the preceding example, in solution in ml 3 gl+of hot isopropanol. The mixture is heated under reflux 45 for 9 hours.It is evaporated to dryness and the residue M -w 233 '37 is treated withacidified water. it is washed with ether, treated again in basic mediumand extracted with ether.

Cl-l OH CO l-l Distillation 20 g of light yellow oil, b.p. l93l95C.Yield 20 g CH (Theoritical yield 36.4 g).

2 I Vapour phase chromatography purity 100 how- 0 ever, the analyticalsample is twice distilled, b.p.

ll77C.

62 g 0.159 mol) of ethyl-a-(5,6,7,8-tetrahydro-1- 55naphthylmethyl)-a-(Z-tetrahydrofurfuryl) I malonate, 22 g (0.39 mol ofKOH and 320 ml of benzyl alcohol are heated under reflux for 8 hours.The solution is evaporated to dryness under vacuum and the semi-solidCalculated 33" gig; Z residue is dissolved in the minimum quantity ofwater Found 74.36 9.58 3.63

Gravimetric analysis (200 ml) and the aqueous layer is washed withhexane. After drying the solution and evaporation to dryness,

there are obtained 27 g of distillable oil, b.p. Infrared CO at 1740 cm205207C. 65 Acid oxalate C H NO M.w. 477.57.

Acidity index: Calculated: 194. Found: 184. 7.74 g (0.02 mol) of theabove ester are dissolved in Infrared, CO badly resolved at l7 l0 and1740 cm 10 ml of acetone. This solution is introduced dropwise Yield 27g 58.5 (theoretical yield 46 g). into a solution of 2.52 g (0.02 mol) ofdihydrated oxalic acid in 10 ml of acetone. A few drops of ether areadded until cloudiness is formed. It is left in the refrigerator andthen suction-filtered. 8.8 g of a white product, m.p. 82-84C, areseparated with a yield of 93 "/1. (theoretical yield 9.5 g). Whenrecrystallised once in a mixture ofdiisopropyl ether and acetone, themelting point remains unchanged Acidity index: Calculated: 234. Found:234.

Gravimetric analysis C 71 H "/1 N 7! Calculated 65.39 8.23 2.93 Found65.35 8.23 3.00

Infrared wide band at 3600 to 3400 cm OH; 1700 to 1720 cm CO.

EXAMPLE 8 Ethyl-a-( 6-meth0xy-Z-naphthylmethyI )-a-(Z-tetrahydrofurfuryl)-malonate H c H 011 0 1 0 co c a 1 l g (0.22 mol)of sodium methylate are suspended in 100 ml of ethyl carbonate and 46.5g (0.191 mol) of ethyl-(Z-tetrahydrofurfuryl)-malonate are introducedthereinto. The exothermic reaction causes the temperature to rise to40C. Following this reaction, heating under reflux takes place for 1hour and then there are introduced 40 g (0.194 mol) of 6-methoxy-2-chloromethylnaphthalene, in solution in 140 ml of ethyl carbonate.Heating under reflux takes place for 1 hour and then there areintroduced 40 g (0.194 mol) of 6-methoxy-2-chloromethylnaphthalene. Insolution in 140 ml of ethyl carbonate. Heating under reflux takes placefor 16 hours and the sodium chloride which forms is dissolved by addingwater. The decanted organic layer is re-washed with water. After dryingand evaporating the solvent, an oily residue is obtained which is takenup in a mixture of 500 ml of water and 125 ml of alcohol. After cooling,the yellow crystals are suction-filtered. Yield 61.4 g 77.5 (theoreticalyield 79 g). M.p. 6061C (softening at 57C).

The product can be used as such. For the analysis, it is recrystallisedfrom hexane M.p. 63-65C (white). The crude oil can be distilled b.p. 1.2to 1.3 millibars 229-23 1C.

Gravimetric analysis C 71 v H '71 Calculated 69.55 7.29 Found 69.58 7.30

I Infrared spectrum: CO at 1730 and 1740 cm EXAMPLE 9 3-(6-Methoxy-2-naphthyl )-2-( 2-tetrahydrofurfuryl propionic acid and thenwith ether. It is acidified with hydrochloric acid. Copious release ofcarbon 'dioxide gas. After scratching, the product crystallises. It ispurified, by extracting it with ether. After drying the organic layerand evaporation to dryness the oily residue is caused to crystallise in100 ml of boiling diisopropyl ether. Yield 20 g 64 (theoretical yield31.4 g). M.p. 100107C. Recrystallisation From 2 g of product in 20 ml ofhexane and ml of diisopropyl ether, there are obtained 1.3 g of m.p.

1 15-l 16C. After a second recrystallisation, the melting point is l 17l19C.

Acidity index: Calculated: 178. Found: 174. Infrared spectrum: CO at1720 cm.

Gravimetric analysis Calculated 72.60 7.05

Found 2.56 7.08

EXAMPLE 10 N-2-Diethylaminoethyl-3-(6-methoxy-2-naphthyl )-2-(2-tetrahydrofurfuryl)-propionate "CH2 CH CQZCHZ CH2 N\ CH I C2115 3 CHl\ N 2 a'be 18 g (0.0575 mol) of the acid of Example 9 are dis- 15 Theivity Of the acid Oxalate of 2- solved in 80 ml of isopropanol, andthere are added thereto 5 g (0.036 mol) of dry K CO followed by asolution of 8 g (0.059 mol) of 2-N-diethylamino chloroethane in 30 ml ofisopropanol. Heating under reflux takes place for 10 hours, whereafterthe solvent is evaporated and the residue is taken up in dilute HCl. Theacid solution is washed with benzene and introduced into alkali mediumand extracted with ether. Distillation yields 10.5 g of an oil, of whichthe boiling point is 230-235C at 1.36 millibars. Yield 10.5 g 44(theoretical yield 23.8 g).

With the second distillation b.p. 235237C at 1.22-1.36 millibars.Infrared spectrum: CO at 1730 cm.

Gravimetric analysis C 72 H N Calculated 72.61 8.53 3.38 Found 72.648.56 3.37

Acid oxalate: C H NO m.w. 503.56.

4.1 g (0.01 mol) of the above base, in 10 ml of acetone, are added to1.3 g (0.01 mol) of dehydrated oxalic acid in 10 ml of acetone. Afterbeing left in the refrigerator and suction-filtered the yield is 5 gquantitative. M.p. 102-l04C. After recrystallisation (ethyl acetate andhexane), the melting point is 102-103C.

Acidity index: Calculated: 223. Found: 220.

Gravimetric analysis C 7r H 71 N 7: Calculated 64.40 7 .40 2.78 Found64.42 7.38 2.77

diethylaminoethyl-3-( 2-naphthyl )-2-( 2-tetrahydrofurfuryl)-propionate(first lot of Example 3) is at least equal to that of the Praxilene. TheLethal Dose (per os mouse) is equal to 1040 mg/kg. The activitycoefficient of the acid oxalate of Z-N-diethylaminoethyl of3-(5,6,7,8-tetrahydrol -naphthyl )-2-( 2- tetrahydrofurfuryl)-propionatein femoral rotametry is equal to 100. The LD (per os mouse) is equal to1350 mg/kg. The activity of the acid oxalate of 2-N-diethylaminoethyl-3-( 6-methoxy-2-naphthyl )-2-( 2-tetrahydrofurfuryl)-propionate in femoral rotametry is 96 The LD (per osmouse) is equal to 2000 mg/kg.

The new active principles present a vasodilatory action at cerebrallevel. it was proved with the dog by measuring the blood flow of twovertebral arteries by means of a Shipley-Wilson ratameter.

The comparison with papaverine administered under the same conditionsdiscloses an activity which is three to four times better with thecompounds of the invention and which is not accompanied by hypotension,as in the case of papaverine.

The daily dose sufficient for obtaining the desired therapeutic resulton human beings varies from about to 300 mg/kg.

It is easy to administer the compounds of the invention thepharmaceutical doses can be formulated in the usual manner with the aidof conventional excipients and adjuvants in the form of tablets,gelatine capsules, injectable solutions, etc.

I claim:

1. A tetrahydrofurfuryl aminoester of formula /C2H5 R CH2 ca CO2CH2 CH2N/ CH CH CO CH CH N 1 I l E 3 2 C2115 C 02H 5. An addition salt of atetrahydrofurfuryl aminocster according to claim 1, with atherapeutically acceptable 391d Oxalate of the ammoester according toid, 10 claim 1, having the formula:

/C H CO l-l R Cl-l lCl-l CO CH Cl-l N\Z 1 I I H CO H

1. A TETRAHYDROFURFURYL AMINOESTER OF THE FORMULA
 2. Atetrahydrofurfuryl aminoester according to claim 1 wherein R is the2-naphthyl-6 methoxy radical.
 3. An addition salt of the compound ofclaim 2, with a therapeutically acceptable acid.
 4. The acid oxalate ofthe aminoester of claim 2, having the formula:
 5. An addition salt of atetrahydrofurfuryl aminoester according to claim 1, with atherapeutically acceptable acid.
 6. An acid oxalate of the aminoesteraccording to claim 1, having the formula: